Higher-order interactions of Bcr-Abl can broaden chronic myeloid leukemia (CML) drug repertoire

Bcr-Abl, a nonreceptor tyrosine kinase, is associated with leukemias, especially chronic myeloid leukemia (CML). Deletion of Abl's N-terminal region, to which myristoyl is linked, renders the Bcr-Abl fusion oncoprotein constitutively active. The substitution of Abl's N-terminal region by Bcr enables Bcr-Abl oligomerization. Oligomerization is critical: it promotes clustering on the membrane, which is essential for potent MAPK signaling and cell proliferation. Here we decipher the Bcr-Abl specific, step-by-step oligomerization process, identify a specific packing surface, determine exactly how the process is structured and identify its key elements. Bcr's coiled coil (CC) domain at the N-terminal controls Bcr-Abl oligomerization. Crystallography validated oligomerization via Bcr-Abl dimerization between two Bcr CC domains, with tetramerization via tight packing between two binary assemblies. However, the structural principles guiding Bcr CC domain oligomerization are unknown, hindering mechanistic understanding and drugs exploiting it. Using molecular dynamics (MD) simulations, we determine that the binary complex of the Bcr CC domain serves as a basic unit in the quaternary complex providing a specific surface for dimer–dimer packing and higher-order oligomerization. We discover that the small α1-helix is the key. In the binary assembly, the helix forms interchain aromatic dimeric packing, and in the quaternary assembly, it contributes to the specific dimer–dimer packing. Our mechanism is supported by the experimental literature. It offers the key elements controlling this process which can expand the drug discovery strategy, including by Bcr CC-derived peptides, and candidate residues for small covalent drugs, toward quenching oligomerization, supplementing competitive and allosteric tyrosine kinase inhibitors.     

Erratum to Central European Journal of Biology, Volume 8, Issue 11

Paper by Li Li Huijuan Wu, Jialin Qian, Mingzhen Li, Yue Li, Baoming Li et al. “Decreased Na+/K+ ATPase α1 (ATP1A1) gene expression in major depression patients’ peripheral blood” in Voulme 8, Issue 11, 1077-1082 / November 2013; DOI: 10.2478/s11535-013-0207-8 contains incorrect units in Figure 3. The correct Figure 3, together with its caption is presented below.     

Study of Displacement Efficiency and Flow Behavior of Foamed Gel in Non-Homogeneous Porous Media

Field trials have demonstrated that foamed gel is a very cost-effective technology for profile modification and water shut-off. However, the mechanisms of profile modification and flow behavior of foamed gel in non-homogeneous porous media are not yet well understood. In order to investigate these mechanisms and the interactions between foamed gel and oil in porous media, coreflooding and pore-scale visualization waterflooding experiments were performed in the laboratory. The results of the coreflooding experiment in non-homogeneous porous media showed that the displacement efficiency improved by approximately 30% after injecting a 0.3 pore volume of foamed gel, and was proportional to the pore volumes of the injected foamed gel. Additionally, the mid-high permeability zone can be selectively plugged by foamed gel, and then oil located in the low permeability zone will be displaced. The visualization images demonstrated that the amoeba effect and Jamin effect are the main mechanisms for enhancing oil recovery by foamed gel. Compared with conventional gel, a unique benefit of foamed gel is that it can pass through micropores by transforming into arbitrary shapes without rupturing, this phenomenon has been named the amoeba effect. Additionally, the stability of foam in the presence of crude oil also was investigated. Image and statistical analysis showed that these foams boast excellent oil resistance and elasticity, which allows them to work deep within formations.     

Distinctive Supercapacitive Properties of Copper and Copper Oxide Nanocrystals Sharing a Similar Colloidal Synthetic Route

CuO and Cu₂O are non‐noble transition metal oxide supercapacitive materials with high theoretical specific capacitances above 1800 F g^?1. In this work, by adjusting organic additives of a colloidal system, Cu, Cu₂O, and CuO are grown in situ on nickel foam. CuO exhibits a specific capacitance of 1355 F g^?1 at 2 A g^?1 in 3 m KOH, a value well above those of Cu and Cu₂O (<500 F g^?1), and is superior to other known CuO electrodes. The CuO electrode exhibits 70% of its initial capacity, and the Columbic efficiency remains ≈100% after 7000 cycles at 4 A g^?1. Cu₂O exhibits the worst electrochemical performance, mainly due to the inactive barrier layer forming on the surface. This work provides an efficient synthetic platform for both comparable supercapacitive studies and cost‐effective electrochemical energy storage applications.     

三峡库区人类活动强度与景观格局的耦合响应

人类活动和景观格局是人地系统中两大要素的重要表征,探析人类活动强度与景观格局的耦合变化特征对揭示区域人地关系的演变意义重大。为弥补当前对人类活动强度与景观格局耦合响应研究的不足,构建了山区人类活动强度与景观格局耦合演变模型,提出了综合显性—隐性人类活动强度指数,定量评价了三峡库区腹地奉节县2000—2020年的人类活动强度,并通过双变量空间自相关模型探讨了综合人类活动强度与景观格局的空间耦合特征。研究表明：(1)奉节县的综合人类活动强度在时间上由2000年的11.59%增加为2020年的12.48%,在空间上表现为整体收缩,局部增强的特点,另外人类活动强度和景观格局的空间分布与奉节县的地形梯度密切相关;(2)奉节县的人类活动强度与景观格局空间耦合变化表现出协调型、拮抗型、逐渐协调型和逐渐拮抗型四种类型;(3)影响奉节县综合人类活动强度与景观格局的耦合变化的重要因子为距聚落距离、距县行政中心距离、高程等,社会经济因素逐渐成为区域社会生态系统演变主导因素;(4)三峡库区腹地人类活动强度与景观格局存在耦合响应,且其耦合响应具有一定的多样性和特殊性。三峡库区腹地通过沟谷土地集约化来换取山区的生...     

Role of IL-17 Variants in Preeclampsia in Chinese Han Women

Previous studies have suggested an important role for IL-17, mainly secreted by Th17 cells, in the development of systemic inflammation in preeclampsia (PE). This study therefore investigated the association between genetic variants in IL-17A, IL-17F, and IL-17RA and susceptibility to PE in Chinese Han women. We recruited 1,031 PE patients and 1,298 controls of later pregnant women, and used TaqMan allelic discrimination real-time PCR to genotype the polymorphisms of IL17A rs2275913, IL-17F rs763780, and IL-17RA rs4819554. No significant differences in genotypic or allelic frequencies were found at all three polymorphic sites between PE patients and controls (rs2275913: genotype χ² = 0.218, p = 0.897 and allele χ² = 0.157, p = 0.692, OR = 1.024, 95%CI 0.911–1.152; rs763780: genotype χ² = 1.948, p = 0.377 and allele χ² = 1.242, p = 0.265, OR = 0.897, 95%CI 0.741–1.086; rs4819554: genotype χ² = 0.633, p = 0.729 and allele χ² = 0.115, p = 0.735, OR = 1.020, 95%CI 0.908–1.146). There were also no significant differences in genetic distributions between mild/severe PE or early/late-onset PE and control subgroups. Our data indicate that the genetic variants of rs2275913 in IL-17A, rs763780 in IL-17F, and rs4819554 in IL-17RA may not play a role in the pathogenesis of PE in Chinese Han women. However, these findings should be confirmed in other ethnic populations.     

Calmodulin and IQGAP1 activation of PI3Kα and Akt in KRAS,HRAS and NRAS-driven cancers

Calmodulin (CaM) binds only oncogenic KRas, but not HRas or NRas, and thus contributes only to KRAS-driven cancers. How CaM interacts with KRas and how it boosts KRAS cancers are among the most coveted aims in cancer biology. Here we address this question, and further ask: Are there proteins that can substitute for CaM in HRAS- and NRAS-driven cancers? Can scaffolding protein IQGAP1 be one? Data suggest that formation of a CaM–KRas–PI3Kα ternary complex promotes full PI3Kα activation, and thereby potent PI3Kα/Akt/mTOR proliferative signaling. CaM binds PI3Kα at the cSH2 and nSH2 domains of its regulatory p85 subunit; the WW domain of IQGAP1 binds cSH2. This raises the question whether IQGAP1, together with an oncogenic Ras isoform, can partially activate PI3Kα. Activated, membrane-bound PI3Kα generates PIP₃. CaM shuttles Akt to the plasma membrane; CaM's release and concomitant phosphoinositide binding stimulates Akt activation. Notably, IQGAP1 directly interacts with, and helps juxtapose, PI3Kα and Akt as well as mTOR. Our mechanistic review aims to illuminate CaM's actions, and help decipher how oncogenic Ras isoforms – not only KRas4B – can activate the PI3Kα/Akt/mTOR pathway at the membrane and innovate drug discovery, including blocking the PI3Kα–IQGAP1 interaction in HRAS- and NRAS-driven cancers.     

Novel mutations in the<Emphasis Type="Italic"> IRF6</Emphasis> gene for Van der Woude syndrome

Van der Woude syndrome (VWS, OMIM 119300) is an autosomal dominant craniofacial disorder characterized by pits of the lower lip, hypodontia, and cleft lip and/or cleft palate. It is the most common form of syndromic orofacial clefting and has very high penetrance with varied expressivity. The disease locus for VWS has been mapped to a 1.6-cM region on 1q32–41 between D1S205 and D1S491. Recently, mutations have been found in the interferon regulatory factor 6 (IRF6) gene in patients with VWS and popliteal pterygium syndrome. To identify novel mutations of IRF6 in VWS patients, we screened four Chinese VWS families in all nine exons and their flanking splice junctions by direct sequencing. We identified three missense mutations and one nonsense mutation in IRF6. Our study further confirmed that IRF6 is essential for craniofacial development.X. Wang and J. Liu contributed equally to this work     

四川青城山穗花杉种群和群落特征的初步研究

本文对四川省都江堰市青城山境内的穗花杉群落进行了初步研究,首次揭示了穗花杉群落和种群的基本特征．穗花杉种群具明显的增长型特征,处于良好的发育状态,其空间分布格局为集群型,其生态习性为显著的耐阴性和岩生性．穗花杉植物群落植物区系成分表现为古老性、残遗性和特有性的有机融合,群落内有维管束植物１１１种．其中热带区系成分占优势．生活型话以常绿高位芽植物为主．而其中又以常绿小高位芽和常绿中高位芽植物占优势．群落中植物叶的性质亦与常绿阔叶林相似。由于常绿针叶植物穗花村在群落中居优势地位,因此作者认为该群落是亚热带常绿阔叶林中的一类特殊群落类型。     

Synthesis and insecticidal evaluation of novel N-pyridylpyrazolecarboxamides containing cyano substituent in the ortho-position

In an attempt to search for potent insecticides targeting the ryanodine receptor (RyR), a series of novel N-pyridylpyrazolecarboxamides containing cyano substituent in the ortho-position were designed and synthesized. Their insecticidal activities of target compounds against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella) indicated that most of the compounds showed moderate to high activities at the tested concentrations. In particular, compound 6l and 6o showed 86% larvicidal activities against Plutella xylostella at the concentration of 0.1 mg/L, while the activity of compound 6h against Mythimna separate was 80% at 1 mg/L. The calcium imaging technique was applied to investigate the effects of some title compounds on the intracellular calcium ion concentration ([Ca²⁺]_i), experimental results demonstrated that compound 6h stimulates a transient elevation in [Ca²⁺]_i in the absence of external calcium after the central neurons dye loading with fluo-3 AM. However, when the central neurons were dyed with fluo-5 N and incubated with 2-APB, [Ca²⁺]i decreased transiently by treated of compound 6h. All of the calcium imaging technique experiments demonstrated that these novel compounds deliver calcium from endoplasmic reticulum to cytoplasm, which proved that the title compounds were the possible activators of insect RyR.